Cathepsin K (Cat K) is a lysosomal cysteine protease that is highly expressed in osteoclasts, the cells responsible for bone degradation during bone remodeling. Type I collagen is a major component of bone and Cat K has high collagenase activity, particularly at the acidic pH that is require to dissolve the calcium hydrocyapatite component of bone. Emerging evidence that Cat K is the primary enzyme involved in osteoclastic bone resorption has made it an important target for the treatment of osteoporosis. Several studies have shown that cat K deficiency leads to an increase in bone mineral density (BMD). Pharmacological studies of Cat K inhibitors in rats and monkeys have shown reductions in biochemical markers of bone resorption and increased BMD (See, e.g. Barrett, F. G. et al., Bioorg. Med. Lett. 12005, 15, 3540; Kumar, S, et al., Bone, 2007, 40, 122).
A variety of cathepsin K inhibitors have been disclosed for the treatment of various disorders related to cathepsin K functioning, including osteoporosis, glucocorticoid induced osteoporosis, Paget's disease, abnormally increased bone turn over, tooth loss, bone fractures, rheumatoid arthritis, osteoarthritis, periprosthetic osteolysis, osteogenesis imperfecta, atherosclerosis, obesity, glaucoma, chronic obstructive pulmonary disease and cancer including metastatic bone disease, hypercalcemia of malignancy, and multiple myeloma. Representative examples of cathepsin K inhibitors, are disclosed in International Publication WO03/075836, which published on Sep. 18, 2003, to Merck & Co., Inc. & Axys Pharmaceuticals, which is hereby incorporated by reference in its entirety.
A particularly effective cathepsin K inhibitor is N1-(1-cyanocyclopropyl)-4-fluoro-N2-{(1S)-2,2,2-trifluoro-1-[4′-(methylsulfonyl)-1,1′-biphenyl-4-yl]ethyl}-L-leucinamide,
which can be prepared by procedures described in: International Publication WO03/075836, which published on Sep. 18, 2003, to Merck & Co., Inc. & Axys Pharmaceuticals; International Publication WO2006/017455, which published on Feb. 16, 2006, to Merck & Co., Inc.; U.S. Publication US2006-0052642, which published on Mar. 9, 2006; U.S. Publication US2005-0234128, which published on Oct. 20, 2005, to Merck & Co., Inc.; all of which are hereby incorporated by reference in their entirety. This compound is also known by its generic name, odanacatib.
Odanacatib, is an orally active, potent and selective Cat K inhibitor currently in development for the treatment of postmenopausal osteoporosis. Odanacatib inhibits human Cat K and has ≧300-fold selectivity against all other known human cathepsins. Studies have shown that odanacatib is well tolerated, and has shown suppression of bone resorption biomarkers when administered in daily and weekly regimens (See, Stoch, S. A. et al., Clinical Pharmacology & Therapeutics, 2009, 86, 175).
It would be desirable to reduce the rate of metabolism of odanacatib. By developing a deuterium substituted analogue of odanacatib, the clearance of the drug can be reduced, thus creating the potential for a drug with a longer half-life.